Cuando hablamos de los efectos positivos de las drogas para la salud, es frecuente encontrarnos con un debate entre los que defienden su uso y los que no.
Especialmente, cuando hablamos de sustancias que tienen un fin lúdico y recreacional, como es ...
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Understanding your endocannabinoid system and the role it plays in your health
Understanding your endocannabinoid system and the role it plays in your health
As the United States finally starts to emerge from the Dark Ages of Cannabis Prohibition, it’s important to shout from the rooftops the scientific fact that the human body was made for cannabis.
In case you didn’t know, your body contains a unique system of receptors that’s designed to utilize the many natural cannabinoids found in cannabis, which in turn facilitates healthy balance and…
According to the findings of several major scientific studies, human breast milk naturally contains of the same cannabinoids found in the cannabis plant, which are vital for proper human development. CBDLife
Dr. Melanie Dreher studied women using cannabis during their entire pregnancy and then studied the babies one year after birth. She found that babies of the women who had smoked cannabis…
Over the last 10 years, a great boost of knowledge accumulated on the immunomodulatory and anti-inflammatory properties of endocannabinoids (eCBs). In this scenario, these bioactive lipids, which are produced by most immune cells along with a set of receptors and enzymes that regulate their synthesis and degradation, act as secondary modulators and increase or decrease a plethora of immune functions. In this review, the manifold immunomodulatory effects of the main eCBs in different compartments of innate and adaptive immunity will be discussed, suggesting that they could be considered as master regulators of innate-adaptive immune axis and as potent immunoresolvents.
Endocannabinoids (eCBs) include a group of lipid mediators, the best characterized of which are N- arachidonoylethanolamine (mostly known as anandamide, AEA) and 2-arachidonoylglycerol (2-AG). Some other compounds have been proposed to belong to the eCB family, including 2-AG-ether (noladin ether) and O-arachidonoylethanolamine (virodhamine), as well as two additional N-acylethanolamines (NAEs), namely N- palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA). eCBs are synthesized and released on demand (if and when needed) from membrane phospholipids in response to physiological or pathological stimuli, although recent evidence has shown that they could be accumulated and stored by intracellular transporters and storage or- ganelles/pools. It is now well established that all body districts and tissues produce eCBs as part of a homeostatic system that acts at almost every level of biological life, with the aim of controlling several physiopathological states and maintaining human health. Their role in the regulation of the immune system is probably the most flourishing and promising research field due to the increasing recognition of the eCBs signaling in several chronic inflammatory diseases.
The majority of scientific studies on the immunoregulatory role of eCBs concentrated on whole immune cells, either on peripheral blood mononuclear cells or on mouse splenocytes.When investigating the specific immunoregulatory role of eCBs on each specific immune cell subset of both innate and adaptive immunity, most of the research has focused on monocytes/macrophages and T cells and mainly on AEA. Of note, AEA is the most potent anti-inflammatory eCB and it practically acts on all cell subsets of either innate or adaptive immunity (except for NK and B cells). Instead, 2-AG exerts both pro- and anti-inflammatory effects and it seems that its effects are strictly dependent on cell type. Although some specific and rarely represented immune cells (i.e., regulatory T cells, cd T cells, or MAIT cells) were never investigated, neither were the subpopulations of each innate immune cell type, it can be generally stated that eCBs, particularly AEA and PEA, could be considered as master regulators of the innate adaptive immune axis and as valuable immunoresolvents. Indeed, the fact that most of these molecules as well as several elements of their metabolism and signaling (i.e., enzymes and receptors) are dysregulated in many pathological states where the immune system is a crucial factor suggests that their exploitation in treating several chronic inflammatory diseases could just be around the corner, providing that their role will be also confirmed in vivo and that their underlying molecular mechanism elucidated.
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Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.
Croton oil administration was associated with decreased levels of anandamide (but not 2-arachidonoyl glycerol) and palmitoylethanolamide, up-regulation of TRPA1 and CB1 receptors and down-regulation of CB2 receptors. Ex vivo CBC did not change endocannabinoid levels, but it altered the mRNA expression of TRPA1 and cannabinoid receptors. In vivo, CBC did not affect motility in control mice, but normalized croton oil-induced hypermotility. In vitro, CBC reduced preferentially EFS- versus ACh-induced contractions. Both in vitro and in vivo, the inhibitory effect of CBC was not modified by cannabinoid or TRPA1 receptor antagonists.
CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.
Cannabichromene (CBC) is, together with D9 -tetrahydrocannabinol, cannabidiol and cannabinol, the most abundant naturally occurring cannabinoid. It is particularly abundant in freshly harvested dry-type Cannabis material and it is the second most abundant cannabinoid in some strains.
[...] CBC was also recently found to stimulate the descending pathway of antinociception in the ventrolateral periaqueductal grey, probably through activation of TRPA1, inhibition of endocannabinoid inactivation and subsequent elevation of local endocannabinoid levels, and possibly via potentiation of adenosine signalling. Both endocannabinoids and TRPA1 are known to be involved in the control of intestinal motility.
[...] Cannabinoids, via enteric CB1 receptor activation in physiological states and via CB2 receptor activation in the inflamed gut, reduce excitatory enteric transmission in vitro and gastrointestinal motility in vivo.
We showed that CBC, a major non-psychotropic component of the marijuana plant, normalizes in vivo intestinal motility in an experimental model of intestinal inflammation, but does not slow the rate of transit in control animals. These protective effects of CBC were accompanied by intestinal changes in cannabinoid and TRPA1 expression, but not of endocannabinoid levels. In vitro results on intestinal ileal segments showed that this phytocannabinoid preferentially reduces EFS-induced contractions – rather than ACh-induced contractions – by a mechanism involving N-type Ca2+ channels. The inhibitory effect of CBC, both in vitro and in vivo, does not involve cannabinoid receptors or TRPA1 channels. Although the precise mechanism of the inhibitory effect of CBC requires further studies, the present results are of potential clinical interest because intestinal dysmotility in inflammatory diseases is a well-recognized and clinically accepted phenomenon, in which the only drugs currently available to counteract it are often associated with constipation. In addition, by revealing that CBC affects the expression of both cannabinoid receptor and TRPA1 mRNA, the present results suggest that the effects of this safe plant compound should be investigated in other pathophysiological conditions (e.g. intestinal secretion, mucosal inflammation, visceral pain and intestinal cancer) in which these receptors are potentially involved.
Chemotherapy-induced nausea is one of the most distressing symptoms reported by patients undergoing treatment, and even with the introduction of newer antiemetics such as ondansetron and aprepitant, nausea remains problematic in the clinic. Indeed, when acute nausea is not properly managed, the cues of the clinic can become associated with this distressing symptom resulting in anticipatory nausea for which no effective treatments are available. In this review, we explore the human and pre-clinical animal literature examining the potential for exogenous and endogenous cannabinoid treatments to regulate chemotherapy-induced nausea. The pre-clinical evidence points to a compelling need to evaluate the antinausea potential of cannabidiol, cannabidiolic acid, and treatments that boost the functioning of the endocannabinoid system in human clinical trials.
[...] Currently, vomiting is relatively well managed in the clinic since the advent of the 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (such as ondansetron) and the neurokinin-1 (NK-1) receptor antagonists (such as aprepitant); however, nausea and anticipatory nausea (a conditioned response through which simply returning to the treatment clinic causes patients to feel nauseous as a result of their association between the contextual cues of the clinic and the nausea they experience from treatment) are still not properly managed.
[...] Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is a high-affinity agonist for both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors and it has been shown to be effective in reducing chemotherapy-induced vomiting9 and/or nausea when smoked or orally administered.
Dronabinol (Marinol), an orally administered synthetic THC, has been shown to be effective in reducing chemotherapy-induced nausea and/or vomiting. In 1985, nabilone (Cesamet), another orally administered synthetic THC, was approved for nausea and vomiting only in patients who were unresponsive to conventional treatments. Nabilone has also been shown to reduce chemotherapy-induced nausea and/ or vomiting.
[...] Most recently, the oromucosal cannabis-based medicine, Sativex (1:1, THC:cannabidiol [CBD]), when combined with the standard treatment of a 5-HT3 antagonist and a corticosteroid, reduced delayed nausea (and vomiting). Because Sativex contains both THC and CBD, it is unknown which compound (or both) contributed to its antinausea effects. Moreover, recent findings in our laboratory indicate that subthreshold doses of THC and cannabidiolic acid (CBDA), the acidic precursor of CBD, when combined, effectively reduce acute nausea and anticipatory nausea in rats; however, we have not investigated whether these effects are mediated by the action of THC at the CB1 receptor, CBDA at the 5-HT1A receptor, or both.
[...] To date, there have been no published clinical trials investigating whether endocannabinoid manipulations (such as increased action of anandamide [AEA] and 2-arachidonylglyercol [2-AG] through enzyme inhibition of fatty acid amide hydrolase [FAAH] or monoacylglycerol lipase [MAGL]) reduce nausea; however, changes in endocannabinoid levels have been measured due to nausea-inducing manipulations. For example, decreases in AEA levels have been reported with administration of the anesthesia sevoflurane, which results in postoperative nausea.42 In addition, reduced levels of AEA and 2-AG have been shown in those experiencing motion sickness. Therefore, it seems that endogenous cannabinoids may be important neuro-modulators involved in the experience of nausea, with decreased levels of AEA and/or 2-AG evident with nausea-inducing manipulations.
The endocannabinoid system clearly plays an important role in the regulation of nausea. The pre-clinical findings suggest that CB1 receptor agonists, as well as FAAH and MAGL inhibitors,which elevate levels of AEA and 2-AG, respectively, reduce acute nausea and anticipatory nausea. As well, by a noncannabinoid mechanism of action, both CBD and CBDA are highly effective antinausea treatments in these animal models without producing sedation or psychoactive effects. Nausea remains an elusive, difficult to control symptom in human chemotherapy patients and there are currently no selective treatments for anticipatory nausea. Clinical trials with FAAH inhibitors, MAGL inhibitors, CBD, and CBDA are warranted to improve the quality of life of patients undergoing cancer treatment by reducing the side effects of nausea and anticipatory nausea when it develops.
